tbuckley/cabot-search huggingface dataset:
Relationship between inflammatory indexes and Khorana score (KS) with prognosis and survival in pancreatic ductal adenocarcinoma (PDAC).
Authors: Rocío Martín Lozano, Roberto Jiménez Rodríguez, Irene Gonzalez Caraballo, Bárbara Lobato Delgado, María Palma Gómez, Marc Ariant Cañete Muñoz, Mónica Benavente de Lucas, Carlos López Jiménez, Victoria Tirado Anula, Blanca Morón García, María de Toro Carmena, Marianela Bringas Beranek, Javier Soto Alsar, Gabriela Torres Pérez-Solero, Aitana Calvo, Laura Ortega, Jose Manuel Soria, Pilar Garcia-Alfonso, Miguel Martin, Andrés J. Muñoz Martín
Journal: Journal of Clinical Oncology (2023)

740 Background: Several inflammatory scores such as the Systemic Inflammation Response Index (SIRI), the Inflammation Index Score (IIS), and the Neutrophil Lymphocyte Ratio (NLR) have been reported to have prognostic value in PDAC with different results. We hypothesize that the KS, designed to predict the risk of cancer-associated thrombosis, may also be a surrogate marker for inflammation to be included as a relevant prognostic index for PDAC. Methods: Baseline characteristics and individual SIRI, IIS, NLR and KS indexes from 197 PDAC patients diagnosed in our center between 2019 and 2021 have been retrospectively recorded. PFS and OS (Log-rank test) have been used to compare the different scores of each index in the whole population as well as in the metastatic setting. Kruskal-Wallis test and Mann-Whitney test were also done to determine if the SIRI varies significantly between KRS values. Results: Of the 197 patients analyzed, 41 were resectable (20.8%), 54 locally advanced (27.4%) and 102 metastatic (51.8%). Patients with intermediate risk according to KS (2 points, n = 131, 66.5%) had a significantly higher median PFS (8.4 vs. 4.8 months, p = 0.03) and significantly higher OS (12.9 vs. 7.7 months, p = 0.002) than those with high-risk (&gt; 3 points, n = 66, 33.5%). The median OS for patients with low (&lt; 3,000) and high (&gt; 3,000) SIRI was 13.1 and 9.3 months respectively (p = 0.05). No significant differences were observed in PFS. In the metastatic setting, a low SIRI was significantly associated with higher OS (10.6 vs. 5.8, p = 0.016). No significant differences were observed in patients with low vs. high IIS and NLR. The Kruskal-Wallis test indicates that SIRI values vary between at least two KS values (p &lt; 0.001). The Mann-Whitney test found significant differences between the SIRI values from S 2 and 3 (p = 0.002) as well as 2 and 4 (p = 0.04). SIRI values were higher in patients with KRS &gt; 3 vs. 2. Conclusions: This retrospective analysis showed that patients with lower KS live longer and progress later than those with higher KS. Lower SIRI is associated with better survival in metastatic patients, being on the verge of statistical significance in the whole cohort. There is a strong correlation between SIRI and KS. In this cohort of unselected PDAC patients, KS is a prognostic factor for OS and PFS that correlates with subclinical inflammation and demonstrates to be a better predictor than other inflammatory indexes that deserves further analysis.
Tissue factor (TF) and factor VII/TF ratio (fVIIa:TF) as potential indicators of malignancy in pancreatic cystic lesions.
Authors: Farzana Haque, Sophie Featherby, Laura Broughton, Pavlos Lykoudis, Kevin Wedgwood, Dowmitra Dasgupta, Sam Khulusi, Abdul Ra, Alexander Buchanan, Chao Huang, Leonid Nikitenko, Camille Ettelaie, Anthony Maraveyas
Journal: Journal of Clinical Oncology (2023)

669 Background: Premalignant pancreatic cellular genotype may remain stable for many years, but compounding conditions can produce rapid malignant cellular transformation. This onset is rarely spontaneous and is often associated with the presence of inflammation. One inflammatory modulator is “tissue factor (TF),” which usually acts in complex with “coagulation factor VIIa (fVIIa)” to initiate coagulation. The role of TF in malignancy and its impact beyond thrombosis on cell proliferation, angiogenesis, and metastasis is well established. This suggests that TF may be a diagnostic marker in the inflammatory microenvironment of the precursor lesions of pancreatic cancer. Aim: To examine the potential of TF concentrations and the fVII:TF ratio within pancreatic cyst fluid as indicators of malignant cellular transformation from benign to malignant. Methods: Cyst fluid was prospectively collected from 31 patients with pancreatic cystic lesions (REC 18/LO/0736) and analysed in a blinded fashion. The level of TF and fVIIa proteins were measured by ELISA, and the fVIIa:TF ratios calculated. A cut-off value for TF concentration was determined using a ROC curve and compared to the conventional assessment parameters, including radiological features, carcinoembryonic antigen (CEA) and amylase. Results: Patients were categorised into four groups based on histology. Significant histological stage-dependent increases in TF level were observed, which corresponded to the progression of the normal ductal epithelium to invasive adenocarcinoma. The mean TF concentration was significantly higher ( p= 0.006) in the high-risk group (high-grade dysplasia &amp; malignant; 1.17 ng/ml, 95% CI 0.68, 1.67) vs the low-risk group (benign &amp; low-grade dysplasia; 0.27 ng/ml, 95% CI 0.1, 0.44). A strong positive correlation between TF concentration and the high-risk group was observed (correlation coefficient 0.746, p &lt; 0.001, the cut-off value for TF 0.75 ng/ml, AUC 0.877, p= 0.002). In addition, the fVIIa:TF ratio, was marginally lower ( p= 0.274) in the high-risk group (mean = 84.82 [95% CI 0, 185.04]) vs the low-risk group (mean = 437.46 [95% CI 0, 901.02]). TF concentrations performed consistently better as an indicator of malignant transformation when compared to the conventional parameters and will be presented at the meeting. Conclusions: Cyst-associated TF levels appear to correlate with the cytological progression to the malignant phenotype, while the fVIIa:TF ratio indicates a breakdown in the ability of the body to contain the disease. Such indicators may allow better presurgical discrimination of malignant potential of tumours and offer a more nuanced tool for monitoring indeterminate cystic lesions. Further work is needed with a larger cohort to confirm these findings.
Development of artificial intelligence–derived histological biomarkers for first-line treatment selection in metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Viswesh Krishna, Ekin Tiu, Vrishab Krishna, Damir Vrabac, Kunal Shah, Waleed Abuzeid, Katelyn Smith, John Davelaar, Christopher Nuesca, Brent K Larson, Christos Fountzilas, Pranav Rajpurkar, Andrew Eugene Hendifar, Eric Andrew Collisson, Anirudh Joshi, Aatur D. Singhi
Journal: Journal of Clinical Oncology (2023)

743 Background: The prognosis of metastatic pancreatic ductal adenocarcinoma (mPDAC) remains poor with a median survival time of 10-12 months. First-line treatment is largely influenced by performance status with fit patients more often receiving FOLFIRINOX (FFX) than Gemcitabine+Nab-Paclitaxel (GNP). Although the two regimens have improved outcomes over gemcitabine monotherapy, no biomarkers routinely used in clinical practice can predict which regimen is optimal to facilitate a precision medicine approach. We developed two signatures (V-FFX and V-GNP) associated with treatment outcomes for the respective first-line regimens using a retrospective cohort of mPDAC cases. Methods: We conducted a retrospective study of mPDAC patients treated at two institutions (UPMC and Cedars Sinai) from 2014 to 2021. Digitized histological H&amp;E sections corresponding to 145 metastatic PDAC patients treated with either first-line FFX or GNP were included. Independent randomized training and test datasets were constructed for FFX-treated (train: 41, test: 25) and GNP-treated (train: 49, test: 30) patients. To construct the histological assay, a deep-learning algorithm then segmented nuclei to extract quantitative histological features. Features associated with disease-specific survival (DSS) for FFX and GNP were identified utilizing univariate Cox proportional hazards (CPH) models for the respective training sets and V-FFX and V-GNP signatures were constructed. DSS stratification of the V-FFX and V-GNP signatures were examined using Kaplan-Meier analysis and the log-rank test and DSS percentages at 12 months were calculated on the respective test sets. Results: The V-FFX and V-GNP signatures were found to be significantly associated with treatment outcomes stratified in the respective test sets (log-rank test, V-FFX: p=0.046, V-GNP: p=0.004). 29 of 55 patients tested positive for only one of either V-FFX and V-GNP signatures. Kaplan-Meier analysis demonstrated robust separation with hazard ratios for the V-FFX and V-GNP signatures of 3.01 (95% CI: 0.96, 9.45) and 4.81 (95% CI: 1.74, 13.3). DSS at 12 months for patients in V-FFX +ve vs -ve groups were 88% (8/9) vs 50% (7/14). DSS at 12 months for patients in V-GNP +ve vs -ve groups were 66% (8/12) vs 15% (2/13). Conclusions: AI derived V-FFX and V-GNP morphological signatures were strongly associated with treatment outcomes for first-line FFX and GNP and can potentially aid in the selection of first-line treatment for mPDAC patients.
Racial, ethnic, and sex-based disparities among high-risk individuals undergoing pancreatic cancer surveillance.
Authors: Kelsey Klute, Aimee L. Lucas, Randall Brand, Jessica N. Everett, James J. Farrell, Kieran Hawthorne, Vivek Kaul, Sonia S. Kupfer, Salvatore Paiella, Diane M. Simeone, Daniel A. Sussman, George Zogopoulos, Fay Kastrinos, Bryson W Katona
Journal: Journal of Clinical Oncology (2023)

687 Background: The international, multi-center Pancreatic Cancer Early Detection (PRECEDE) Consortium enrolls high-risk individuals (HRIs) undergoing pancreatic ductal adenocarcinoma (PDAC) surveillance. Enrollment began in 2020, and despite challenges related to the COVID-19 pandemic, the PRECEDE Consortium rapidly accrued a large cohort of HRIs. The purpose of this study is to describe the characteristics of this cohort and assess racial, ethnic, and sex-based disparities. Methods: The PRECEDE Consortium (NCT04970056) is a prospective, multicenter study focused on improving survival from PDAC through early detection. Data from all HRIs who met criteria for PDAC surveillance and enrolled between May 2020 - March 2022 were collected and included in the analysis. Results: During the study period, 1299 HRIs enrolled in PRECEDE at 32 centers. HRIs were excluded if enrollment data was incomplete or criteria for PDAC surveillance were not met. Of 1113 who were included, 47.2% met criteria for familial pancreatic cancer (FPC) and 45.4% had a family history of PDAC along with a PV in a PDAC-risk gene (BRCA1, BRCA2, PALB2, ATM, MLH1, MSH2, MSH6, PMS2, or EPCAM). The remainder had familial atypical mole melanoma syndrome (5.7%), Peutz-Jeghers syndrome (1.6%), or hereditary pancreatitis (0.2%). More females than males enrolled (65.9% vs. 33.5%). The distribution of HRIs by race and ethnicity is depicted; the majority identified as white (87.7%). Study participants were primarily from the US (82.7%), the median age was 61 (27-85) and 18.5% had Ashkenazi Jewish ancestry. Nearly all HRIs consented to allow access to imaging data (99.6%), collection of germline DNA (97.7%), and biosample collection (99.5%). There were no race, ethnicity, or sex-based differences in rates of consent for collection of imaging, DNA, or biosamples. Conclusions: Enrollment of HRIs in prospective studies of PDAC surveillance is essential for advancing early detection research in PDAC. A distinct advantage of the PRECEDE Consortium for examining enrollment disparities is that recruitment began in 2020, providing a unique and current snapshot of the international PDAC surveillance landscape. Despite the recent attention on addressing disparities in healthcare delivery, significant racial, ethnic, and sex-based disparities persisted in the cohort of HRIs enrolled in the PRECEDE Consortium. Ensuring that the diversity of participants in the PRECEDE Consortium mirrors the communities served by participating centers is crucial. Further examining and addressing the reasons for these disparities is a major focus of the PRECEDE Consortium moving forward. [Table: see text]
Extending surgical resection for hepatocellular carcinoma beyond Barcelona Clinic for Liver Cancer (BCLC) stage A: A novel application of the modified BCLC staging system.
Authors: Ian Wee, Fiona Moe, Rehena Sultana, Reiko Ang, Pearly Quek, Brian Goh, Chung Yip Chan, Peng Chung Cheow, Alexander Chung, Prema Raj, Ye Xin Koh, Peter Mack, London Lucien Ooi, Ek Khoon Tan, Jin Yao Teo, Juinn Huar Kam, Jacelyn Chua, Ashley Ng, Jade Goh, Pierce K. H. Chow
Journal: Journal of Clinical Oncology (2023)

503 Background: Intermediate hepatocellular carcinoma is a heterogenous group of disease. We aimed to prognosticate survival after surgical resection of HCC stratified by stage with amalgamation of the modified Barcelona Clinic Liver Cancer (BCLC) staging system and location of tumour. Methods: This single-institutional retrospective cohort study included patients with HCC who underwent surgical resection between 1 st January 2000 to 30 th June 2016. Participants were divided into 6 different subgroups based on the Milan Criteria (MC), the “Up-to-7” criteria, and location of lesions: A-u) Within MC with Unilobar lesions; A-b) Within MC + Bilobar lesions; B1-u) Out of MC + within Up-To-7 + Unilobar lesions; B1-b) Out of MC + within Up-to-7 + Bilobar lesions; B2-u) Out of MC + Out of Up-To-7 + Unilobar lesions; B2-b) Out of MC + Out of Up-To-7 + Bilobar lesions. A separate survival analysis was conducted for solitary HCC lesions according to three subgroups: A-S (Within MC); B1-S (Out of MC + within Up-To-7); B2-S (Out of MC + out of Up-To-7). The respective primary and secondary time-to-event outcomes were overall survival (OS) and recurrence-free survival (RFS). Results: 794 of 1043 patients with surgical resection for HCC were analysed. Groups A-u (64.6 %), A-b (58.4 %) and B1-u (56.2 %) had 5-year cumulative overall survival (OS) rates above 50% after surgical resection and median OS exceeding 60 months (P=0.0001). The 5-year cumulative recurrence-free survival rates (RFS) were 40.4% (group A-u), 38.2% (group A-b), 36.3% (group B1-u), 24.6% (group B2-u), and 7.3% (group B2-b)(P=0.0001). For solitary lesions, the 5-year OS for the subgroups were A-S (65.1%), B1-S (56.0%) and B2-S (47.1%) (P=0.0003). Compared to A-S, there was also a significant trend towards relatively poorer OS as the lesion sizes increased in B1-S (HR 1.46, 95%CI 1.03 – 2.08) and B2-S (HR 1.65, 95%CI 1.25 – 2.18). Conclusions: We adopted a novel approach combining the modified BCLC B sub-classification and dispersion of tumour to show that surgical resection may be curative in a select subgroup of patients with intermediate HCC that fall outside BCLC Stage A, specifically those with unilobar lesions and are within the “up-to-7” criteria. Furthermore, We found that size prognosticates resection outcomes in solitary tumours.
HERIZON: A phase 2 study of HER-Vaxx (IMU-131), a HER2-targeting peptide vaccine, plus standard of care chemotherapy in patients with HER2-overexpressing metastatic or advanced gastric/GEJ adenocarcinoma— Overall survival analysis.
Authors: Marina Maglakelidze, Dinara E. Ryspayeva, Zoran Andric, Zoran Petrovic, Iurie Bulat, Ivan Nikolic, Rajnish Nagarkar, Ursula Wiedermann, Brent A. Blumenstein, Leslie Mi Ok Chong, Nicholas Ede, Bonnie Nixon, Sharon Yavrom, Giovanni Selvaggi, Anthony J. Good, Tanuj Chawla
Journal: Journal of Clinical Oncology (2023)

289 Background: Active immunization with the B-lymphocyte stimulating HER2 vaccine, HER-Vaxx (IMU-131), has shown clinical response correlated with HER2-specific antibodies (Wiedermann et. al., Clinical Cancer Research, 2021). The HER-Vaxx HERIZON study is based on the landmark ToGA study (Bang et. al., The Lancet, 2010) and included patients with HER2/neu over-expressing metastatic or advanced gastric/GEJ adenocarcinoma who were naïve to HER2 therapy. Methods: Thirty-six patients were randomized to either HER-Vaxx plus standard chemotherapy or standard chemotherapy alone. The primary endpoint was overall survival (OS). HER-Vaxx plus chemotherapy treated patients received 50 µg dose of HER-Vaxx by intra-muscular injection at Days 0, 14, 35, 77 and every 63 days until disease progression. Both groups received chemotherapy starting at Day 0 and then every 21 days for a maximum of 6 cycles or until disease progression. Standard chemotherapy consisted of cisplatin + 5FU or capecitabine, or oxaliplatin + capecitabine. Statistical analysis pre-specified a 1-sided false positive probability of 0.10. Results: Of 36 patients randomized (19 treated with HER-Vaxx plus chemotherapy and 17 with chemotherapy alone), 32 patients had a survival event (15 and 17 respectively) at the time of final analysis. All patients received oxaliplatin + capecitabine chemotherapy. Analysis showed a 42% survival benefit for patients treated with HER-Vaxx plus chemotherapy compared to chemotherapy alone. This translated into an OS HR of 0.580 (80% 2-sided CI: 0.362, 0.927) with a statistically significant p-value of 0.066. The median OS for patients receiving HER-Vaxx plus chemotherapy was 13.9 (7.5, 14.3) months, compared to 8.3 (6.0, 9.6) months in patients treated with chemotherapy alone. Median duration of response was 30 vs 19 weeks in favor of the HER-Vaxx arm. There was no difference in safety between the two treatment arms, indicating HER-Vaxx does not add toxicity to standard chemotherapy. HER-Vaxx induced persistent HER2 specific antibodies which correlated with clinical response. Additional response parameters including DOR and biomarker data will be presented at the meeting. Conclusions: These data demonstrate that in patients with HER2 over-expressing gastric/GEJ cancer active HER2 immunization with HER-Vaxx is safe and provides relevant clinical benefit over standard of care chemotherapy. Clinical trial information: NCT02795988 .
The optimal extent of lymph node dissection for gastric cancer with para-aortic lymph node metastases.
Authors: Takeyuki Wada, Takaki Yoshikawa, Kenichi Ishizu, Tsutomu Hayashi, Yukinori Yamagata
Journal: Journal of Clinical Oncology (2023)

413 Background: Gastric cancer (GC) with para-aortic lymph node (PAN) metastasis is diagnosed as stage IV and basically treated with chemotherapy. Recently, D2 and PAN dissection after neoadjuvant chemotherapy (NAC) was reportedly effective when PAN metastasis was limited within #16a2/b1 area. However, PAN dissection is highly invasive surgical procedure and it still remains unclear whether PAN dissection contributes to the survival for these tumors. This study aimed to determine the optimal extent of lymph node dissection for these tumors focusing on survival benefit of PAN dissection. Methods: The study examined patients who received radical gastrectomy with D2 and PAN dissection after NAC for gastric cancer with PAN metastasis (#16a2/b1) from 2004 to 2015. Survival benefit of lymph node dissection was estimated using therapeutic value index (TI). TI was calculated by multiplication of incidence of metastasis and 5-year survival rate of patients with metastasis for each lymph node area. TI of D2 dissection area (TI-D2) and PAN area (TI-PAN) was calculated separately. Overall survival (OS) was calculated in patients who had metastasis to PAN pathologically after surgery (pPAN+ group) and those who had not (pPAN- group). The recurrence site was also examined. Results: Thirty-two patients were analyzed. TI-D2 and TI-PAN were 15.6 and 0.0, respectively. 5y-OS was 81.0% in pPAN- group (21 cases) but was 0.0% in pPAN+ group (11 cases). The most frequent recurrence site was the lymph nodes (82.4% of all recurrences). Among lymph node recurrence, almost all recurrence patterns included the PANs (85.7% of lymph node recurrence). Conclusions: The prognosis was extremely poor when tumor cells remained on PAN after NAC. In these cases, PAN recurrence was seen most frequently even after PANs had been dissected. Patients with PAN could have the chance for the cure only when tumor cells on PAN was completely eliminated by NAC. It is unclear whether they actually needed PAN dissection for pathologically negative PAN. The optimal extent of lymph node dissection after NAC might be D2 for GC with PAN metastasis.
Gene expression profiles in Hispanic patients with early-onset gastric cancer.
Authors: Michelle R Ju, Changjin Hong, John D Karalis, Suntrea Hammer, Matthew R. Porembka, Tae Hyun Hwang, Sam C. Wang
Journal: Journal of Clinical Oncology (2023)

464 Background: A larger proportion of Hispanic gastric cancer patients are diagnosed at a young age than patients of other ethnicities. Despite diagnosis at an early age, young Hispanic patients also present more frequently with advanced disease. Whether there are molecular differences between tumors from young and old Hispanic gastric cancer patients is unknown. Methods: We performed RNA-sequencing on pre-treatment tumor samples of gastric cancer patients of self-identified Hispanic ethnicity. We stratified patients into two groups: &lt;50 years and ≥50 years. Differentially expressed genes between groups were detected using the DESeq2 package (RStudio). We performed Gene Set Enrichment Analysis (GSEA) to identify pathways that were uniquely overexpressed in each age group. Results: 57 patients were included in our study. 23 patients were &lt;50 years and 33 patients were ≥50 years. Comparison of the top 10% most differentially expressed genes showed no clustering based on age. However, visual inspection of the top 40 most differentially expressed genes revealed 2 distinct patterns of gene expression between age groups. GSEA revealed upregulation of DNA replication, cell cycle, and DNA repair pathways in the younger patients The tumors in younger patients also had upregulation of multiple immune activation pathways. Cancers from older patients had upregulation of programmed cell death pathways. Conclusions: Early-onset gastric cancer in Hispanic patients may represent a distinct biologic process.